Bisulphite derivatives of 2-methyl-1, 4-naphthoquinone and the like



Patented Jan. 16, 1-945 linrsunrnrrnl DE li Drawin v The present invention 'relates to pharmaceutical compositions and mor' p'articularly to water:- .s lub e fih e lnen li j nenes hav n vitamin'K activity. ,It hasbeenshownby animaltestsand'clinical investigations ,f that vzeinethyl 1ylenaphtl oquinone possesses great; itami'riQK ,activityi '.A t..

mums; 5 1,4-NAPHTHOQUINONE 'lHE LIKE Mirior le nimble-spa Frederick JfiKirchiiieyer, "Waukegan, llL-yassignors to Abbott Labor-a rams, North' chic'a' go, Ill., corporation of lllilpplication" March'Z S i j serialNas zasoo j slclaimsri (CL260 396) v tempts, however, 'toluse-thislproduct, i e, methyln phth u ne fse';h net rce e e y 'satis factory. It'fwas found, rgrjexampie, that satisfactory concentrations could'not be obtained for parenteral administration due to the extremely mwsommmy of the naphthoquinonesin suitable tsolvents. ..It was also jfoundj that the naphtho- Iquinon e products were relatively \uns table and that the products had a; ndency t n r a hange in vitaminpotency whenstored for some I jTherefore, the. principal object of, the L present ent on s tep evid fl w evel e he c compositions of the type-desired A more specific object or thepresentinvention i t previlde zrmeth l-m-n hth e befi onsew mh- 18. ta le a eous o u n of t d sired t ns-fe p re te ala ministrationriu i a OF ti-mum; I

i-"Ill the above examples, Example 13.:empl0ys vmolar equivalents of sodium bisulphite andz2- methyl-1;4@-naphth0quinone, and Examplell employs 2 ,molar equivalents of potassium bisulphite tol molar equivalent of 2-methyl-l,4t-naphtho.- c uinone. These examples representingpreferred ratios ofyingredients are merely illustrative and are not to be interpreted as limiting. I V 3111].: place of the alkali metal saltsusedh infithe above illustrative examples other, water. soluble bisulphite salts mayb substituted thereforeincludingthe alkalin earth metal salts such'as calcium bisulphite. Other suitablesaltsare the ni- ,trogen salts including the ammoniumsalt as well Other objects of thefpresentinvention willbe I i Examples of suitable alkyl groupsjinclude the apparent as the description hereinafter proceeds. Wehavediscovered that bisulphites ii e.,- water ,q ub e bis ite S s e yed it en comp unds with alkyl substituted naphthoquinones and that such addition compounds possess-in; available .iorm the desired vitamin activity We have also discovered that 2 the f bisulphite addition cornmpounds have. a-much greater watersolubility than the naphthoquinone; product: itself. and-that this increase: in solubility provides meansfor readily obtaining solutions of the desired concentrations vfor. parenteraladministration-t We have further discovered that the addition compounds as well as solutions v.of the sameiare stable and that they retain the original vitamin. potency for 7 long periods-ottime... s 1. a The compounds'of the present, invention may be prepared by-mixing. the alkylsubstituted naphthoquinone with the rbisulphite saltying the presas thesubstituted ammoniumsalts including the primary,-v secondary and tertiary alkyl and substituted allryl amine v bisulphites and the corresponding f quaternary ammonium bisulphites.

mono-,1 di v triand tetra-methyl, ethyl, propyl, butyli m l e l. eta, m Sa siwe lve h corresponding: hydroxy alkylor. alkanol amine same ,The tphenylt e kyl a ines, e, g., benzylamine, aswell, as the aromatic amines, e. g.,ani:- line, may also be employed Inaddition tothe above the cycloalkyl amines may. be; employed including the cycloalkyl groups in which the N is an element of a. heterocyclic. ring. 'Qthenheter'ocyclic aminescontaininga thirdelementfin the encepflwuater.v v,Qrclinarilygentle warming-or th aqueous mixture is preferredto facilitate solution. The following representative examples which may be prepared as indicated above will serve to illustrate the present invention:

ring such as morpholine in'ay alsovv be used. h

r While,{as indicated were, any, water soluble bisulphite salt'may be used to solubilize and stabilize th naphthoquinone, the sbdium- -Na, calciiini-Ca, YethanOIamine-HOCHCHQNI-I'z, diethylamine -(Czl-ls) 2N H, diethyl. hydroxy ethyland n-vbut IQmj-nB CQHQNHZ, bisulphitexI-ISOa) saltsare representative types of :preferred species. Salts such as barium bisulphitewhile operative .are not preferred due to the relatively high toxic- The bisulphite addition compounds of the present invention have been found to be stable in sunlight and also to be heat stable. Tests, for example, carried out in ampoules have shown aqueous solutions of the compounds not to be decomposed after exposure to a month's sunlight, while other tests have shown the solutions or the preierred compounds to retain their original potency (a) when stored in an oven at 60 C. for 15 days or (b) when sterilized at 15 pounds for 0.5 hour in an autoclave at about 122 C. These properties emphasize the radical diiferences between the stable compounds of the present invention and the properties of 2-methyl-L4-naphthoquinone, the characteristic instability of which is illustrated by its sensitivity, 1. e., decomposition, when exposed to light. Several tests including the freezing point test have demonstrated that the novel compositions of the present invention are true chemical compounds of the bisulphite salt and alkyl substituted naphthoquinone. The interaction and change of solubility is adequately illustrated by the fact that the higher alkyl amine bisuliites, such as lauryl amine bisuliite, form by themselves cloudy soapy solutions which upon addition of the relatively insoluble naphthoquinone change to clear sparkling solutions.

The dilute aqueous solutions of most of the compounds (e. g., containing 1 mg. of naphthoquinone per c. c.) made up of molecular equivalents of bisulphite salt and 2-methyl-1,4-naphthoquinone show a slight trace of yellow color while like solutions made up of 2 mols of bisulphite to 1 mol of 2-methyl-1,4-naphthoquinone are for the most part substantially water clear, 1. e., colorless. The concentrated solutions (e. g., /2 and 1 molar solutions) on the other hand show a definite light yellow color while solutions of the ammonium salt possess a reddish color.

The solutions containing the larger proportions of bisulphite salt (e. g., Example II) are ordinarily preferred as they are more heat stable and thus permit higher sterilization temperature than the solutions containing smaller proportions of bisulphite salt. The smaller amounts of bisulphite salt, e. g., in 1 mol proportion or less, may be used, however, to advantage as the bisulphite even when present in less than 1 mol proportion increases the solubility of naphthoquinone and aids in stabilizing the solutions. Similarly larger amounts of bisulflte salt, e. g., 2.5 or 3 mol proportions, may be used although the use of amounts above the 2:1 ratio of bisulphite to naphthoquinone are not accompanied by propor-- tional advantages in the pharmaceutical art.

The bisulphite addition compounds or complexes of the present invention have a vitamin K activity equal to that of the 2-methyl-1,4-naphthoquinone contained in the molecule or complex. The compounds, although suitable for oral administration, are particularly adaptable in aqueous solution for parenteral administration in the treatment of hemorrhagic conditions.

The present invention employing a watersoluble salt characterized by the presence of the H80: group may be used to solubilize and stabilize various naphthoquinones although it is particularly adaptable for use with the alkyl substituted na hthoquinones having antihemorrhagic activity. It will be therefore understood that the present invention is not limited to the above illustrative examples. All modifications coming within the scope of the present invention are intended to be covered by the following claims.

memos We claim:

1. The method solubilizing and stabilizing an anti-hemorrhagic naphthoquinone, which consists in mixing an unstable and relatively insoluble 2-methyl- 1,4-naphthoquinone with a nontoxic water-soluble bisulphite salt in water, and thereby solubilizing and stabilizing said naphthoquinone withoutimpairment of its vitamin K properties.

2. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-L4-naphthoquinone with an alkali metal bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of v said product being substantially equivalent to that of the 2-methyl-1,4-naphthoquinone present therein.

3. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with a sodium bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of said product being substantially equivalent to that of the 2-methyl-1,4-naphthoquinone present therein.

4. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with a sodium bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of said product being substantially equivalent to that of the 2-methyI-L4-naphthoquinone present therein.

5. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with an alkaline earth metal bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of said product being substantially equivalent to that of the 2-methyl-L4-naphthoquinone present therein.

6. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with a calcium bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity 01 said product being substantially equivalent to that of the 2-methyl-1,4-naphthoquinone present therein.

7. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with an alkanol amine bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of said product being substantially equivalent to that of the 2-methyl-1,4-naphthoquinone present therein.

8. A pharmaceutical composition containing as an essential ingredient, an addition product, dissolved in water, of 2-methyl-1,4-naphthoquinone with an ethanolamine bisulphite salt, said product being characterized by solubility and stability satisfactory for parenteral use, the vitamin K activity of said product being substantially equivalent to that of the 2-methyl-1,4-naphthoquinone present therein.

MARJORIE B. MOORE. FREDERICK J. KIRCI-IMEYER. 

